tbuckley/cabot-search huggingface dataset:
Quantitative live-cell imaging of lipidated peptide transport through an epithelial cell layer
Authors: Adam Coln Hundahl, Arjen Weller, Jannik Bruun Larsen, Claudia U. Hjørringgaard, Morten B. Hansen, Ann-Kathrin Mündler, Astrid Knuhtsen, Kasper Kristensen, Eva C. Arnspang, Thomas Lars Andresen, Kim I. Mortensen, Rodolphe Marie
Journal: Journal of Controlled Release (2023)

Oral drug delivery increases patient compliance and is thus the preferred administration route for most drugs. However, for biologics the intestinal barrier greatly limits the absorption and reduces their bioavailability. One strategy employed to improve on this is chemical modification of the biologic through the addition of lipid side chains. While it has been established that lipidation of peptides can increase transport, a mechanistic understanding of this effect remains largely unexplored. To pursue this mechanistic understanding, end-point detection of biopharmaceuticals transported through a monolayer of fully polarized epithelial cells is typically used. However, these methods are time-consuming and tedious. Furthermore, most established methods cannot be combined easily with high-resolution live-cell fluorescence imaging that could provide a mechanistic insight into cellular uptake and transport. Here we address this challenge by developing an axial PSF deconvolution scheme to quantify the transport of peptides through a monolayer of Caco-2 cells using single-cell analysis with live-cell confocal fluorescence microscopy. We then measure the known cross-barrier transport of several compounds in our model and compare the results with results obtained in an established microfluidic model finding similar transport phenotypes. This verifies that already after two days the Caco-2 cells in our model form a tight monolayer and constitute a functional barrier model. We then apply this assay to investigate the effects of side chain lipidation of the model peptide drug salmon calcitonin (sCT) modified with 4‑carbon and 8‑carbon-long fatty acid chains. Furthermore, we compare that with experiments performed at lower temperature and using inhibitors for some endocytotic pathways to pinpoint how lipidation length modifies the main avenues for the transport. We thus show that increasing the length of the lipid chain increases the transport of the drug significantly but also makes endocytosis the primary transport mechanism in a short-term cell culture model.
Genomic Underpinnings of Population Persistence in Isle Royale Moose
Authors: Christopher C Kyriazis, Annabel C Beichman, Kristin E Brzeski, Sarah R Hoy, Rolf O Peterson, John A Vucetich, Leah M Vucetich, Kirk E Lohmueller, Robert K Wayne
Journal: Molecular Biology and Evolution (2023)

Island ecosystems provide natural laboratories to assess the impacts of isolation on population persistence. However, most studies of persistence have focused on a single species, without comparisons to other organisms they interact with in the ecosystem. The case study of moose and gray wolves on Isle Royale allows for a direct contrast of genetic variation in isolated populations that have experienced dramatically differing population trajectories over the past decade. Whereas the Isle Royale wolf population recently declined nearly to extinction due to severe inbreeding depression, the moose population has thrived and continues to persist, despite having low genetic diversity and being isolated for ∼120 years. Here, we examine the patterns of genomic variation underlying the continued persistence of the Isle Royale moose population. We document high levels of inbreeding in the population, roughly as high as the wolf population at the time of its decline. However, inbreeding in the moose population manifests in the form of intermediate-length runs of homozygosity suggestive of historical inbreeding and purging, contrasting with the long runs of homozygosity observed in the smaller wolf population. Using simulations, we confirm that substantial purging has likely occurred in the moose population. However, we also document notable increases in genetic load, which could eventually threaten population viability over the long term. Overall, our results demonstrate a complex relationship between inbreeding, genetic diversity, and population viability that highlights the use of genomic datasets and computational simulation tools for understanding the factors enabling persistence in isolated populations.
Retroperitoneal Inflammation Detected on FDG PET/CT in Patient on Long-Term Immunotherapy
Authors: Tasnim Khessib, Benjamin Franc, Eric Yang, Farshad Moradi
Journal: Clinical Nuclear Medicine (2023)

A 68-year-old man with a history of pulmonary adenocarcinoma on maintenance pembrolizumab presented for surveillance imaging. 18 F-FDG PET/CT demonstrated new ill-defined right retroperitoneal and presacral soft tissue stranding with associated FDG uptake suggestive of inflammation. Biopsy results revealed fibroadipose tissue with extensive lymphoplasmacytic inflammation concerning for immunotherapy-related toxicity. The patient was subsequently taken off pembrolizumab, which he had been on for approximately 3 years. Recognition of immunotherapy-related adverse effects and how they can manifest on 18 F-FDG PET/CT is important for prompt cessation of treatment.
Increased Tumor Mutation Burden Levels and Sensitivity of Non–Small Cell Lung Cancer to PD-L1 Blockade
Authors: Xinmu Zhang, Li Zhang
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Cervix Abscess Mimicking Cervical Cancer Explored With 18F-FDG PET/CT and MRI
Authors: Anthony Dhomps, Alexis Trecourt, Jeremie Tordo
Journal: Clinical Nuclear Medicine (2023)

Abstract We report the case of a 32-year-old woman gravida 2 para 2 with pelvic pain evolving for 2 months, who underwent imaging examinations, including 18 F-FDG PET/CT and MRI, which showed a tumor-like cervix tissular mass with pathological lymph nodes and pelviperitonitis. An endocervical curettage with conization revealed a bacterial infection with cervical abscess and without neoplastic component. The follow-up 18 F-FDG PET/CT 3 months after starting antibiotherapy confirmed a complete metabolic and morphological response of the cervical abscess.
Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in<i>EGFR</i>-Mutant Lung Adenocarcinomas
Authors: Arielle Elkrief, Alex Makhnin, Khadeja A. Moses, Linda S. Ahn, Isabel R. Preeshagul, Afsheen N. Iqbal, Sara A. Hayes, Andrew J. Plodkowski, Paul K. Paik, Marc Ladanyi, Mark G. Kris, Gregory J. Riely, Franziska Michor, Helena A. Yu
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. Patients and Methods: We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. Results: Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%–88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%–58%). Conclusions: We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.
Minimising school disruption under high incidence conditions due to the Omicron variant in France, Switzerland, Italy, in January 2022
Authors: Elisabetta Colosi, Giulia Bassignana, Alain Barrat, Bruno Lina, Philippe Vanhems, Julia Bielicki, Vittoria Colizza
Journal: Eurosurveillance (2023)

BackgroundAs record cases of Omicron variant were registered in Europe in early 2022, schools remained a vulnerable setting undergoing large disruption.AimThrough mathematical modelling, we compared school protocols of reactive screening, regular screening, and reactive class closure implemented in France, in Baselland (Switzerland), and in Italy, respectively, and assessed them in terms of case prevention, testing resource demand, and schooldays lost.MethodsWe used a stochastic agent-based model of SARS-CoV-2 transmission in schools accounting for within- and across-class contacts from empirical contact data. We parameterised it to the Omicron BA.1 variant to reproduce the French Omicron wave in January 2022. We simulated the three protocols to assess their costs and effectiveness for varying peak incidence rates in the range experienced by European countries.ResultsWe estimated that at the high incidence rates registered in France during the Omicron BA.1 wave in January 2022, the reactive screening protocol applied in France required higher test resources compared with the weekly screening applied in Baselland (0.50 vs 0.45 tests per student-week), but achieved considerably lower control (8% vs 21% reduction of peak incidence). The reactive class closure implemented in Italy was predicted to be very costly, leading to > 20% student-days lost.ConclusionsAt high incidence conditions, reactive screening protocols generate a large and unplanned demand in testing resources, for marginal control of school transmissions. Comparable or lower resources could be more efficiently used through weekly screening. Our findings can help define incidence levels triggering school protocols and optimise their cost-effectiveness.
Recommendations on the use of item libraries for patient-reported outcome measurement in oncology trials: findings from an international, multidisciplinary working group
Authors: Claire Piccinin, Ethan Basch, Vishal Bhatnagar, Melanie Calvert, Alicyn Campbell, David Cella, Charles S Cleeland, Corneel Coens, Anne-Sophie Darlington, Amylou C Dueck, Mogens Groenvold, Ralf Herold, Bellinda L King-Kallimanis, Paul G Kluetz, Dagmara Kuliś, Daniel O'Connor, Kathy Oliver, Madeline Pe, Bryce B Reeve, Jaap C Reijneveld, Xin Shelley Wang, Andrew Bottomley
Journal: The Lancet Oncology (2023)
Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Carsten Denkert, Chiara Lambertini, Peter A. Fasching, Katherine L. Pogue-Geile, Max S. Mano, Michael Untch, Norman Wolmark, Chiun-Sheng Huang, Sibylle Loibl, Eleftherios P. Mamounas, Charles E. Geyer, Peter C. Lucas, Thomas Boulet, Chunyan Song, Gail D. Lewis, Malgorzata Nowicka, Sanne de Haas, Mark Basik
Journal: Clinical Cancer Research (2023)

In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined.T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32-3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56-1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44-1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59-1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
Acute Coronary Occlusion in Patients With Non-ST-Segment Elevation Out-of-Hospital Cardiac Arrest
Authors: Alessandro Spirito, Lukas Vaisnora, Athanasios Papadis, Fortunato Iacovelli, Celestino Sardu, Alexandra Selberg, Sarah Bär, Raminta Kavaliauskaite, Fabrice Temperli, Babken Asatryan, Thomas Pilgrim, Lukas Hunziker, Dik Heg, Marco Valgimigli, Stephan Windecker, Lorenz Räber
Journal: Journal of the American College of Cardiology (2023)
Increased PSMA Expression in 177Lu-PSMA-617 Scan in Metastatic Castrate-Resistant Prostate Cancer Patient Treated With PSMA Radioligand Therapy and Enzalutamide
Authors: Piyush Aggarwal, Komalpreet Kaur, Ashwani Sood, Kannan Periasamy, Shreya Nagi, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2023)

Abstract Androgen deprivation therapy plays an integral role in the treatment algorithm of advanced prostate cancer. Enzalutamide has shown great benefit in castrate-sensitive as well as resistant prostate cancer. Few studies have shown that enzalutamide can potentially increase the PSMA expression on 68 Ga-PSMA-11 PET/CT imaging in patients with metastatic castrate-resistant prostate cancer. We present an interesting case where addition of short course of enzalutamide resulted in increased localization of 177 Lu-PSMA-617 in metastatic lesions on posttherapy scan pointing to the added benefit of PSMA RLT.
A Discordant Pattern of Uptake on 68Ga-PSMA PET/CT Versus 18F-Fluciclovine PET/CT in Radiation-Induced Hepatitis
Authors: Omotayo A. Adediran, Ismaheel O. Lawal, Saima Muzahir, Manali A. Bhave, Sarah Friend, Bridget Fielder, Jane Meisel, Mylin A. Torres, Toncred M. Styblo, Cathy Graham, Anna Holbrook, Kevin Kalinsky, Ronald J. Crowe, Gary A. Ulaner, David M. Schuster
Journal: Clinical Nuclear Medicine (2023)

A 62-year-old woman with right-sided invasive lobular breast carcinoma completed external beam radiotherapy 6 weeks before undergoing a 68 Ga-PSMA PET/CT and 18 F-fluciclovine PET/CT scan as part of an ongoing clinical trial (NCT04750473) assessing the performance of these molecular imaging modalities in invasive lobular breast carcinoma. The 68 Ga-PSMA PET/CT demonstrated a band-like area of increased radiotracer uptake in the dome of the right lobe of the liver anteriorly, whereas 18 F-fluciclovine PET/CT done a day later revealed photopenia in the corresponding area of the liver. The external beam radiotherapy plan confirmed that the radiotherapy field overlaid the region of the hepatic discordant radiotracer uptake on the PET/CT scans.
Incidental Diagnosis of Metastatic Breast Cancer in a Man With 99mTc-PSMA SPECT/CT
Authors: César D. Zárate-García, David R. Cardoza-Ochoa, Yazmín Sánchez-Vera, Jorge Iván González-Díaz
Journal: Clinical Nuclear Medicine (2023)

Breast cancer in men is a rare and unsuspected malignancy. A 48-year-old man begins with disabling low back pain. The CT scan reported a compression fracture in L2 and diffuse skeletal lesions suggestive of metastatic disease. The serum prostate-specific antigen was 6.2 ng/mL. He was referred for SPECT/CT with 99m Tc-EDDA/HYNIC-inhibitor prostate-specific membrane antigen due to clinical suspicion of prostate cancer. SPECT/CT with 99m Tc-EDDA/HYNIC-inhibitor prostate-specific membrane antigen showed a primary lesion in the left breast and multiple bone lesions. Biopsy confirmed infiltrating ductal carcinoma with positive hormone receptors and indeterminate HER2 (human epidermal growth factor receptor 2).
Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates
Authors: Fang Wei, Yuling Su, Yibo Quan, Xiaojia Li, Qi Zou, Liuxi Zhang, Shu Li, Mengmeng Jiang, Guohuan Lin, Ping Liang, Jie He, Keping Xie
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying this resistance will improve PDA immunotherapy. This study investigated therapeutic effects and underlying mechanisms of anticoagulants on immunotherapy in PDA. Experimental Design: The antitumor activity of immunotherapy was evaluated in mouse models of desert, excluded, and inflamed tumors. The underlying mechanisms were investigated by analyzing immune cell infiltration by immunofluorescence imaging and tumor microcirculation by interstitial fluid pressure and coagulation status measurement. Results: Combined use of heparin and ACT inhibited tumor growth and metastasis, whereas neither heparin nor ACT had any therapeutic effect. The combination of heparin and ACT significantly increased the intratumor infiltration of CD8+ T cells and M1 macrophages and reduced the infiltration of immunosuppressive M2 macrophages and FOXP3+/CD4+ regulatory T cells (Treg). Assessments of tumor microenvironment revealed that heparin promoted tumor vascular regression and normalized the remaining blood vessels, facilitating the extravasation and perivascular accumulation of activated CD8+ T cells in tumors. Mechanistically, tumor microvessel hemodynamic properties were significantly improved by heparin, which is consistent with its inhibitory effects on tumor angiogenesis. Similarly, the combination of heparin and anti-PD1 also produced a pronounced antitumor activity, whereas neither heparin nor anti-PD1 treatment had appreciable antitumor activity. Conclusions: Combined treatment of heparin and ACT or anti-PD1 produced synergistic antitumor effects, which were at least in part through tumor vascular normalization, hence increased antitumor T-cell responses due to reduced Treg infiltration and increased M1 macrophage polarization. This synergistic combination therapy warrants clinical evaluation. See related commentary by Korc, p. 2348
68Ga-FAPI-04 PET/CT In Primary Signet Ring–Like Cell Carcinoma of Prostate With Bone Metastases
Authors: Gamze Tatar, Sevim Baykal Koca, İsa Sevindir, Nurhan Ergül, Tevfik Fikret Çermik
Journal: Clinical Nuclear Medicine (2023)

We presented a 69-year-old man with liver cirrhosis who underwent 68 Ga-fibroblast activation protein (FAPI)-04 PET/CT imaging for an ongoing study. In addition to the significant activity in liver cirrhosis on FAPI PET, a primary prostate tumor was incidentally detected with bone metastases. Further, FAPI-negative metastases were not observed on CT evaluation. In this context, we think that FAPI may be helpful with the potential theranostic aspect, especially in selected patients when current treatment options are not applicable or unresponsive. However, we should await the results of prospective studies investigating both prognostic and theranostic use of FAPI and demonstrating its effectiveness in cancer therapy.
Hepatic Small Vessel Neoplasm Mimics Prostate Cancer on 18F-DCFPyl PET/CT
Authors: Keith L. Spinali, David J. Papke, Hina J. Shah
Journal: Clinical Nuclear Medicine (2023)

18 F-DCFPyl is a Food and Drug Administration-approved radiotracer that targets prostate-specific membrane antigen and is used in the detection of recurrent or metastatic prostate cancer. As its use has increased, a growing number of nonprostatic disease entities have been identified that express prostate-specific membrane antigen and can mimic prostate cancer. Thus, the interpreting physician must also consider other variables such as serum prostate-specific antigen levels and the distribution of uptake to avoid an inappropriate diagnosis of metastatic prostate cancer. We describe 18 F-DCFPyl uptake associated with a hepatic small vessel neoplasm, an association previously undescribed in the literature.
Dual-Time-Point 18F-FDG PET/CT for Differentiating a Chest Wall Hemangioma From a Malignant Metastasis
Authors: Hsi-Huei Lu, Nan-Tsing Chiu
Journal: Clinical Nuclear Medicine (2023)

Dual-time-point 18 F-flluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) can be used to differentiate benign vascular tumors from other malignant growths. We present the case of a 70-year-old woman with a history of cervical carcinoma who was referred for PET/CT to examine a left chest wall tumor noted on CT, which involved the adjacent rib and pleura, thus raising the suspicion of metastasis. The chest wall tumor demonstrated moderate FDG uptake and further decreased uptake at the delayed-phase scanning, corresponding to biodistribution of FDG in the blood pool. These findings indicated a benign hemangioma rather than a metastasis.
Asymptomatic Prostate Cancer Metastasis in Rectal Mucosa Revealed by 18F-PSMA-1007 PET/CT
Authors: Shu Wang, Zhiming Cheng, Bulin Du, Yaming Li, Xuena Li
Journal: Clinical Nuclear Medicine (2023)

Abstract Prostate cancer metastasis to the rectal mucosa, a relatively rare metastatic site, leads to a higher clinical stage and poorer prognosis. A 65-year-old man with prostate cancer underwent 18 F–prostate-specific membrane antigen (PSMA) PET/CT for staging. Intense 18 F-PSMA uptake occurred at the primary lesion, bladder, adjacent seminal vesicle, and rectum. PET/CT imaging revealed increased homogeneous round activity of the rectal wall. The final diagnosis was prostate cancer metastasis to the rectal mucosa. This case suggested that 18 F-PSMA PET/CT may assist in locating rare metastases of prostate cancer, with potential value for early staging.